tbuckley/cabot-search huggingface dataset:
Controlled intracellular aggregation of magnetic particles improves permeation and retention for magnetic hyperthermia promotion and immune activation
Authors: Ao Hu, Yiyao Pu, Na Xu, Zhongyuan Cai, Ran Sun, Shengxiang Fu, Rongrong Jin, Yingkun Guo, Hua Ai, Yu Nie, Xintao Shuai
Journal: Theranostics (2023)

Rationale: Magnetic nanoparticles (MNPs) are the most used inorganic nanoparticles in clinics with therapeutic and imaging functions, but the inefficient magneto-thermal conversion efficiency, fast leakage, and uneven distribution impair their imaging sensitivity and therapeutic efficacy in tumors.Methods: Herein, we rationally designed a system containing pH-controllable charge-reversible MNPs (M20@DPA/HA) and negatively charged MMPs with different sizes (M5 and M20), which could induce intracellular aggregation.The dynamic hydrazone bonds with pH controllability were formed by the surface hydrazides on MNPs and aldehydes of hyaluronic acid (HA).Under the acidic pH, intracellular aggregation of the complex composed by M20@DPA/HA and M5 (M5&20), or M20@DPA/HA and M20 (M20&20) were investigated.In addition, the magnetic hyperthermia therapy (MHT) efficiency of tumor cells, tumor-associated macrophages polarization, giant cells formation and immune activation of tumor microenvironment were explored via a series of cell and animal model experiments.Results: Through physical and chemical characterization, the aggregation system (M20&20) exhibited a remarkable 20-fold increase in magnetothermal conversion efficiency compared to individual MNPs, together with enhanced penetration and retention inside the tumor tissues.In addition, it could promote immune activation, including repolarization of tumor-associated macrophages, as well as the formation of giant cells for T cell recruitment.As a result, the M20&20 aggregation system achieved a high degree of inhibition in 4T1 mouse mammary tumor model, with little tumor growth and metastasis after magnetic hyperthermia therapy.Conclusions: A controlled intracellular aggregation system was herein developed, which displayed an aggregation behavior under the acidic tumor microenvironment.The system significantly enhanced MHT effect on tumor cells as well as induced M1 polarization and multinucleated giant cells (MGC) formation of TAM for immune activation.This controlled aggregation system achieved barely tumor growth and metastasis, showing a promising strategy to improve MNPs based MHT on deteriorate cancers.
Histological diagnosis of unprocessed breast core-needle biopsy via stimulated Raman scattering microscopy and multi-instance learning
Authors: Yifan Yang, Zhijie Liu, Jing Huang, Xiangjie Sun, Jianpeng Ao, Bin Zheng, Wanyuan Chen, Zhiming Shao, Hao Hu, Yinlong Yang, Minbiao Ji
Journal: Theranostics (2023)

Core-needle biopsy (CNB) plays a vital role in the initial diagnosis of breast cancer.However, the complex tissue processing and global shortage of pathologists have hindered traditional histopathology from timely diagnosis on fresh biopsies.In this work, we developed a full digital platform by integrating label-free stimulated Raman scattering (SRS) microscopy with weakly-supervised learning for rapid and automated cancer diagnosis on un-labelled breast CNB.Methods: We first compared the results of SRS imaging with standard hematoxylin and eosin (H&E) staining on adjacent frozen tissue sections.Then fresh unprocessed biopsy tissues were imaged by SRS to reveal diagnostic histoarchitectures.Next, weakly-supervised learning, i.e., the multi-instance learning (MIL) model was conducted to evaluate the ability to differentiate between benign and malignant cases, and compared with the performance of supervised learning model.Finally, gradient-weighted class activation mapping (Grad-CAM) and semantic segmentation were performed to spatially resolve benign/malignant areas with high efficiency.Results: We verified the ability of SRS in revealing essential histological hallmarks of breast cancer in both thin frozen sections and fresh unprocessed biopsy, generating histoarchitectures well correlated with H&E staining.Moreover, we demonstrated that weakly-supervised MIL model could achieve superior classification performance to supervised learnings, reaching diagnostic accuracy of 95% on 61 biopsy specimens.Furthermore, Grad-CAM allowed the trained MIL model to visualize the histological heterogeneity within the CNB. Conclusion:Our results indicate that MIL-assisted SRS microscopy provides rapid and accurate diagnosis on histologically heterogeneous breast CNB, and could potentially help the subsequent management of patients.
Twist1 downregulation of PGC-1α decreases fatty acid oxidation in tubular epithelial cells, leading to kidney fibrosis: Erratum
Authors: Limin Liu, Xiaoxuan Ning, Lei Wei, Ying Zhou, Lijuan Zhao, Feng Ma, Ming Bai, Xiaoxia Yang, Di Wang, Shiren Sun
Journal: Theranostics (2023)

[This corrects the article DOI: 10.7150/thno.71722.].
Epigenetically regulated lncRNAs dissect the intratumoural heterogeneity and facilitate immune evasion of glioblastomas
Authors: Dahua Xu, Meng Cao, Bo Wang, Xiaoman Bi, Haiying Zhang, Deng Wu, Chunrui Zhang, Jiankai Xu, Zhizhou Xu, Dehua Zheng, Liyang Chen, Peihu Li, Hong Wang, Yan Liu, Hongyan Jiang, Kongning Li
Journal: Theranostics (2023)

Glioblastomas are the most common and malignant central nervous system (CNS) tumors that occupied a highly heterogeneous tumor microenvironment (TIME). Long noncoding RNAs (lncRNAs), whose expression can be modified by DNA methylation, are emerging as critical regulators in the immune system. However, knowledge about the epigenetic changes in lncRNAs and their contribution to the immune heterogeneity of glioma is still lacking.
Imaging DNA damage response by γH2AX <i>in vivo</i> predicts treatment response to Lutetium-177 radioligand therapy and suggests senescence as a therapeutically desirable outcome
Authors: Edward O'Neill, Michael Mosley, Bart Cornelissen
Journal: Theranostics (2023)

Rationale: An effective absorbed dose response relationship is yet to be established for Lutetium-177 based radionuclide therapies such as 177 Lu-DOTATATE and 177 Lu-PSMA.The inherent biological heterogeneity of neuroendocrine and prostate cancers may make the prospect of establishing cohort-based dose-response relationships unobtainable.Instead, an individual-based approach, monitoring the dose-response within each tumor could provide the necessary metric to monitor treatment efficacy.Methods: We developed a dual isotope SPECT imaging strategy to monitor the change over time in the relationship between 177 Lu-DOTATATE and 111 In-anti-γH2AX-TAT, a modified radiolabelled antibody that allows imaging of DNA double strand breaks, in mice bearing rat pancreatic cancer xenografts.The dynamics of γH2AX foci, apoptosis and senescence following exposure to 177 Lu-DOTATATE was further investigated in vitro and in ex vivo tumor sections. Results:The change in slope of the 111 In-anti-γH2AX-TAT to 177 Lu signal between days 5 and 7 was found to be highly predictive of survival (r = 0.955, P < 0.0001).This pivotal timeframe was investigated further in vitro: clonogenic survival correlated with the number of γH2AX foci at day 6 (r = -0.995,P < 0.0005).While there was evidence of continuously low levels of apoptosis, delayed induction of senescence in vitro appeared to better account for the γH2AX response to 177 Lu.The induction of senescence was further investigated by ex vivo analysis and corresponded with sustained retention of 177 Lu within tumor regions.Conclusions: Dual isotope SPECT imaging can provide individualized tumor dose-responses that can be used to predict lutetium-177 treatment efficacy.This bio-dosimeter metric appears to be dependent upon the extent of senescence induction and suggests an integral role that senescence plays in lutetium-177 treatment efficacy.
KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8<sup>+</sup> T-cell-dependent antitumor immunity
Authors: Qi Wu, Zhou Liu, Zhijie Gao, Yao Luo, Fubing Li, ChuanYu Yang, Tiantian Wang, Xiangyu Meng, Haijun Chen, Juanjuan Li, Yanjie Kong, Chao Dong, Si Sun, Ceshi Chen
Journal: Theranostics (2023)

Background: Immune checkpoint blockers (ICBs) are revolutionized therapeutic strategies for cancer, but most patients with solid neoplasms remain resistant to ICBs, partly because of the difficulty in reversing the highly immunosuppressive tumor microenvironment (TME).Exploring the strategies for tumor immunotherapy is highly dependent on the discovery of molecular mechanisms of tumor immune escape and potential therapeutic target.Krüppel-like Factor 5 (KLF5) is a cell-intrinsic oncogene to promote tumorigenesis.However, the cell-extrinsic effects of KLF5 on suppressing the immune response to cancer remain unclear. Methods:We analyzed the immunosuppressive role of KLF5 in mice models transplanted with KLF5-deleted/overexpressing tumor cells.We performed RNA sequencing, immunohistochemistry, western blotting, real time-PCR, ELISA, luciferase assay, chromatin immunoprecipitation (ChIP), and flow cytometry to demonstrate the effects of KLF5 on CD8 + T cell infiltration and related molecular mechanism.Single-cell RNA sequencing and spatial transcriptomics analysis were applied to further decipher the association between KLF5 expression and infiltrating immune cells.The efficacy of KLF5/COX2 inhibitors combined with anti-programmed cell death protein 1 (anti-PD1) therapy were explored in pre-clinical models.Finally, a gene-expression signature depending on KLF5/COX2 axis and associated immune markers was created to predict patient survival.Results: KLF5 inactivation decelerated basal-like breast tumor growth in a CD8 + T-cell-dependent manner.Transcriptomic profiling revealed that KLF5 loss in tumors increases the number and activated function of T lymphocytes.Mechanistically, KLF5 binds to the promoter of the COX2 gene and promotes COX2 transcription; subsequently, KLF5 deficiency decreases prostaglandin E2 (PGE2) release from tumor cells by reducing COX2 expression.Inhibition of the KLF5/COX2 axis increases the number and functionality of intratumoral antitumor T cells to synergize the antitumorigenic effects of anti-PD1 therapy.Analysis of patient datasets at single-cell and spatial resolution shows that low expression of Ivyspring International
Multiparametric magnetic resonance imaging for radiation therapy response monitoring in soft tissue sarcomas: a histology and MRI co-registration algorithm
Authors: Matthias Jung, Balazs Bogner, Thierno D. Diallo, Suam Kim, Philipp Arnold, Hannah Füllgraf, Konrad Kurowski, Peter Bronsert, Pia M. Jungmann, Jurij Kiefer, Daniel Kraus, Philipp Rovedo, Marco Reisert, Steffen U. Eisenhardt, Fabian Bamberg, Matthias Benndorf, Alexander Runkel
Journal: Theranostics (2023)

Rationale:To establish a spatially exact co-registration procedure between in vivo multiparametric magnetic resonance imaging (mpMRI) and (immuno)histopathology of soft tissue sarcomas (STS) to identify imaging parameters that reflect radiation therapy response of STS.Methods: The mpMRI-Protocol included diffusion-weighted (DWI), intravoxel-incoherent motion (IVIM), and dynamic contrast-enhancing (DCE) imaging.The resection specimen was embedded in 6.5% agarose after initial fixation in formalin.To ensure identical alignment of histopathological sectioning and in vivo imaging, an ex vivo MRI scan of the specimen was rigidly co-registered with the in vivo mpMRI.The deviating angulation of the specimen to the in vivo location of the tumor was determined.The agarose block was trimmed accordingly.A second ex vivo MRI in a dedicated localizer with a 4 mm grid was performed, which was matched to a custom-built sectioning machine.Microtomy sections were stained with hematoxylin and eosin.Immunohistochemical staining was performed with anti-ALDH1A1 antibodies as a radioresistance and anti-MIB1 antibodies as a proliferation marker.Fusion of the digitized microtomy sections with the in vivo mpMRI was accomplished through nonrigid co-registration to the in vivo mpMRI.Co-registration accuracy was qualitatively assessed by visual assessment and quantitatively evaluated by computing target registration errors (TRE). Results:The study sample comprised nine tumor sections from three STS patients.Visual assessment after nonrigid co-registration showed a strong morphological correlation of the histopathological specimens with ex vivo MRI and in vivo mpMRI after neoadjuvant radiation therapy.Quantitative assessment of the co-registration procedure using TRE analysis of different pairs of pathology and MRI sections revealed highly accurate structural alignment, with a total median TRE of 2.25 mm (histology -ex vivo MRI), 2.22 mm (histology -in vivo mpMRI), and 2.02 mm (ex vivo MRI -in vivo mpMRI).There was no significant difference between TREs of the different pairs of sections or caudal, middle, and cranial tumor parts, respectively.Conclusion: Our initial results show a promising approach to obtaining accurate co-registration between histopathology and in vivo MRI for STS.In a larger cohort of patients, the method established IvyspringInternational Publisher here will enable the prospective identification and validation of in vivo imaging biomarkers for radiation therapy response prediction and monitoring in STS patients via precise molecular and cellular correlation.
Nasopharyngeal carcinoma ecology theory: cancer as multidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem
Authors: Weiren Luo
Journal: Theranostics (2023)

Nasopharyngeal carcinoma (NPC) is a particular entity of head neck cancer that is generally regarded as a genetic disease with diverse intertumor and intratumor heterogeneity. This perspective review mainly outlines the up-to-date knowledge of cancer ecology and NPC progression, and presents a number of conceptual stepping-stones. At the beginning, I explicitly advocate that the nature of NPC (cancer) is not a genetic disease but an ecological disease: a multidimensional spatiotemporal "unity of ecology and evolution" pathological ecosystem. The hallmarks of cancer is proposed to act as ecological factors of population fitness. Subsequently, NPC cells are described as invasive species and its metastasis as a multidirectional ecological dispersal. The foundational ecological principles include intraspecific relationship (e.g. communication) and interspecific relationship (e.g. competition, predation, parasitism and mutualism) are interpreted to understand NPC progression. "Mulberry-fish-ponds" model can well illustrate the dynamic reciprocity of cancer ecosystem. Tumor-host interface is the ecological transition zone of cancer, and tumor buddings should be recognized as ecological islands separated from the mainland. It should be noted that tumor-host interface has a significantly molecular and functional edge effect because of its curvature and irregularity. Selection driving factors and ecological therapy including hyperthermia for NPC patients, and future perspectives in such field as "ecological pathology", "multidimensional tumoriecology" are also discussed. I advance that "nothing in cancer evolution or ecology makes sense except in the light of the other". The cancer ecology tree is constructed to comprehensively point out the future research direction. Taken together, the establishment of NPC ecology theory and cancer ecology tree might provide a novel conceptual framework and paradigm for our understanding of cancer complex causal process and potential preventive and therapeutic applications for patients.
Xeno-free cultured mesenchymal stromal cells release extracellular vesicles with a “therapeutic” miRNA cargo ameliorating cartilage inflammation <i>in vitro</i>
Authors: Maria Elisabetta F. Palamà, Simona Coco, Georgina M. Shaw, Daniele Reverberi, Maddalena Ghelardoni, Paola Ostano, Giovanna Chiorino, Laura Sercia, Luana Persano, Maria Cristina Gagliani, Katia Cortese, Dario Pisignano, Josephine Mary Murphy, Chiara Gentili
Journal: Theranostics (2023)

Rationale: Mesenchymal stromal cells (MSCs)-derived extracellular vesicles (EVs) emerged as an innovative strategy for the treatment of chronic disorders such as osteoarthritis (OA).Biological activity of EVs is generally driven by their cargo, which might be influenced by microenvironment.Therefore, pre-conditioning strategies, including modifications in culture conditions or oxygen tension could directly impact on MSCs paracrine activity.In this study we selected an appropriate preconditioning system to induce cells to perform the most suitable therapeutic response by EV-encapsulated bioactive factors.Methods: A xeno-free supplement (XFS) was used for isolation and expansion of MSCs and compared to conventional fetal bovine serum (FBS) culture.Bone Marrow-derived MSCs (BMSCs) were pre-conditioned under normoxia (20% O2) or under hypoxia (1% O2) and EVs production was evaluated.Anti-OA activity was evaluated by using an in vitro inflammatory model.miRNA content was also explored, to select putative miRNA that could be involved in a biological function.Results: Modulation of IL-6, IL-8, COX-2 and PGE2 was evaluated on hACs simultaneously treated with IL-1α and BMSC-derived EVs.FBS-sEVs exerted a blunt inhibitory effect, while a strong anti-inflammatory outcome was achieved by XFS-sEVs.Interestingly, in both cases hypoxia pre-conditioning allowed to increase EVs effectiveness.Analysis of miRNA content showed the upregulation in XFS-hBMSC-derived EVs of miRNA known to have a chondroprotective role, such as let-7b-5p, miR-17, miR-145, miR-21-5p, miR-214-3p, miR-30b-5p, miR-30c-5p.Activated pathways and target genes were investigated in silico and upregulated miRNAs functionally validated in target cells.MiR-145 and miR-214 were found to protect chondrocytes from IL-1α-induced inflammation and to reduce production of pro-inflammatory cytokines.Conclusions: XFS medium was found to be suitable for isolation and expansion of MSCs, secreting EVs with a therapeutic cargo.The application of cells cultured exclusively in XFS overcomes issues of safety associated with serum-containing media and makes ready-to-use clinical therapies more accessible.
FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC
Authors: Xilang Chen, Jie Chen, Weibo Feng, Wenjie Huang, Guodong Wang, Mengyu Sun, Xiangyuan Luo, Yijun Wang, Yongzhan Nie, Daiming Fan, Kaichun Wu, Limin Xia
Journal: Theranostics (2023)

Background: Metastasis accounts for the high lethality of colorectal cancer (CRC) patients. Unfortunately, the molecular mechanism manipulating metastasis in CRC is still elusive. Here, we investigated the function of E74-like factor 4 (ELF4), an ETS family member, in facilitating CRC progression. Methods: The expression of ELF4 in human CRC samples and CRC cell lines was determined by quantitative real-time PCR, immunohistochemistry and immunoblotting. The migratory and invasive phenotypes of CRC cells were evaluated by in vitro transwell assays and in vivo metastatic models. The RNA sequencing was used to explore the downstream targets of ELF4. The luciferase reporter assays and chromatin immunoprecipitation assays were used to ascertain the transcriptional regulation related to ELF4. Results: We found elevated ELF4 was positively correlated with distant metastasis, advanced AJCC stages, and dismal outcomes in CRC patients. ELF4 expression was also an independent predictor of poor prognosis. Overexpression of ELF4 boosted CRC metastasis via transactivating its downstream target genes, fibroblast growth factor receptor 4 (FGFR4) and SRC proto-oncogene, non-receptor tyrosine kinase, SRC. Fibroblast growth factor 19 (FGF19) upregulated ELF4 expression through the ERK1/2/SP1 axis. Clinically, ELF4 expression had a positive correlation with FGF19, FGFR4 and SRC, and CRC patients who positively coexpressed FGF19/ELF4, ELF4/FGFR4, or ELF4/SRC exhibited the worst clinical outcomes. Furthermore, the combination of the FGFR4 inhibitor BLU-554 and the SRC inhibitor KX2-391 dramatically suppressed ELF4-mediated CRC metastasis. Conclusions: We demonstrated the essentiality of ELF4 in the metastatic process of CRC, and targeting the ELF4-relevant positive feedback circuit might represent a novel therapeutic strategy.
Nanoparticle formulations for therapeutic delivery, pathogen imaging and theranostic applications in bacterial infections
Authors: Lai Jiang, Linyu Ding, Gang Liu
Journal: Theranostics (2023)

Pathogenic bacterial infections represent an ever-growing crisis, now significantly threatening life expectancy across the worldwide population and thus novel approaches to tackle this issue are urgently needed.The application of nanotechnology in recent years has opened up new horizons in the selective or specific delivery of drugs or imaging agents to infectious sites.In particular, the development of nanoparticles for both delivery of active substances and imaging of infection sites is now gathering much interest.Although still in its infancy, the field of antibacterial nanomedicines provides exciting new possibilities to combat multi-resistant bacterial infections and shows great promise for personalized medicine in antibacterial stewardship.This review examines nanoparticle-based formulations used for therapeutic delivery, pathogen tracking in diagnosis, and combined "theranostic" approaches to more effectively treating bacterial infections.
Abnormal expression of MUC1 apomucin and mature MUC1 mucin in biliary epithelial cells in various cystic liver diseases
Authors: M Sasaki, Y Nakanuma
Journal: Hepatology (1996)

MUC1 apomucin is proposed as an “oncofetal” antigen in the biliary system. We surveyed the biliary expression of MUC1 apomucin and mature MUC1 mucin (highly–glycosylated MUC1 apomucin) in hepatic cysts, biliary microhamartomas, and intrahepatic bile ducts in various cystic liver diseases and clarified the relationship between the expression of these mucins and cystogenesis in the liver. The expression of MUC1 apomucin and mature MUC1 mucin were detected immunohistochemically using the monoclonal antibodies DF3 and SM3, and HMFG1, respectively. We surveyed six livers with adult–type polycystic disease (APCD), six with multiple hepatic cysts without polycystic kidney, 11 with solitary hepatic cysts, and 11 “histologically normal” livers. Biliary microhamartomas were frequently found in the former three. MUC1 apomucin was frequently expressed at the luminar surface of the epithelial cells lining cysts and also in biliary microhamartomas, independent of the type of cystic disease. MUC1 apomucin detected by both monoclonal antibodies (MAbs) DF3 and SM3 was also frequently expressed in the intrahepatic bile ducts from polycystic diseases, particularly the adult–type, whereas such expression was rare in the intrahepatic bile ducts in normal livers. Mature MUC1 mucin was expressed on the luminal surface of the epithelial cells lining cysts in approximately half of hepatic cysts studied, but it was infrequently expressed in biliary microhamartomas and almost absent in the intrahepatic bile ducts. The biliary epithelial cells lining hepatic cysts, biliary microhamartomas, the apparently normal intrahepatic bile ducts in APCD, multiple hepatic cysts, and to a lesser degree, solitary hepatic cysts, express abnormal levels MUC1 apomucin. This implies that biliary epithelial cells expressing MUC1 apomucin are related to the whole cystogenetic process in these diseases. In contrast, the expression of mature MUC1 mucin may be related to the late cystogenetic process in these diseases.